Analytical system and method

ABSTRACT

An analytical or preparatory system comprised as a base unit, an adapter, and a substrate. The adapter is attached to an attachment region on the base unit, and the substrate is attached to an attachment region on the adapter. The adapter permits the base unit to be interfaced with a wide variety of different substrates to perform chemical and biological analytical analyses and preparatory procedures.

This application is a continuation-in-part of application Ser. No.08/691,632, filed on Aug. 2, 1996, the full disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to systems and methods forperforming chemical and biological analyses. More particularly, thepresent invention relates to the design and use of an analyzer systemwhich employs analytical substrates evaluated in a base unit, where anadapter is used as an interface between the substrate and the base unit.

Numerous systems and instruments are available for performing chemical,clinical, and environmental analyses of chemical and biologicalspecimens. Conventional systems may employ a variety of detectiondevices for monitoring a chemical or physical change which is related tothe composition or other characteristic of the specimen being tested.Such instruments include spectrophotometers, fluorometers, lightdetectors, radioactive counters, magnetometers, galvanometers,reflectometers, ultrasonic detectors, temperature detectors, pressuredetectors, mephlometers, electrophoretic detectors, PCR systems, LCRsystems, and the like. Such instruments are often combined withelectronic support systems, such as microprocessors, timers, videodisplays, LCD displays, input devices, output devices, and the like, ina stand-alone analyzer. Such analyzers may be adapted to receive asample directly but will more usually be designed to receive a sampleplaced on a sample-receiving substrate, such as a dipstick, cuvette,analytical rotor or the like. Usually, the sample-receiving substratewill be made for a single use (i.e. will be disposable), and theanalyzer will include the circuitry, optics, sample manipulation, andother structure necessary for performing the assay on the substrate. Asa result, most analyzers are intended to work only with a single type ofsample-receiving substrate and are not readily adaptable to be used withother substrates.

Recently, a new class sample-receiving substrate has been developed,referred to as "microfluidic" systems. Microfluidic substrates havenetworks of chambers connected by channels which have mesoscaledimensions, where at least one dimension is usually between 0.1 μm and500 μm. Such microfluidic substrates may be fabricated usingphotolithographic techniques similar to those employed in thesemiconductor industry, and the resulting devices can be used to performa variety of sophisticated chemical and biological analyticaltechniques. Microfluidic analytical technology has a number ofadvantages, including the ability to employ very small sample sizes,typically on the order of nanoliters. The substrates may be produced ata relatively low cost, and can be formatted to perform numerous specificanalytical operations, including mixing, dispensing, valving, reactions,and detections.

Because of the variety of analytical techniques and potentially complexsample flow patterns that may be incorporated into particularmicrofluidic test substrates, significant demands may be placed on theanalytical units which support the test substrates. The analytical unitsnot only have to manage the direction and timing of flow through thenetwork of channels and reservoirs on the substrate, they may also haveto provide one or more physical interactions with the samples atlocations distributed around the substrate, including heating, cooling,exposure to light or other radiation, detection of light or otheremissions, measuring electrical/electrochemical signals, pH, and thelike. The flow control management may also comprise a variety ofinteractions, including the patterned application of voltage, current,or power to the substrate (for electrokinetic flow control), or theapplication pressure, acoustic energy or other mechanical interventionsfor otherwise inducing flow.

It can thus be seen that a virtually infinite number of specific testformats may be incorporated into microfluidic test substrates. Becauseof such variety and complexity, many if not most of the test substrateswill require specifically configured analyzers in order to perform aparticular test. Indeed, it is possible that particular test substratesemploy more than one analyzer for performing different tests. The needto provide one dedicated analyzer for every substrate and test, however,will significantly reduce the flexibility and cost advantages of themicrofluidic systems.

It would therefore be desirable to provide improved analytical systemsand methods which overcome or substantially mitigate at least some ofthe problems set forth above. In particular, it would be desirable toprovide analytical systems including base analytical units which cansupport a number of different microfluidic or other test substrateshaving substantially different flow patterns, chemistries, and otheranalytical characteristics. It would be particularly desirable toprovide analytical systems where the cost of modifying a base analyticalunit to perform different tests on different test substrates issignificantly reduced.

2. Description of the Background Art

Microfluidic devices for analyzing samples are described in thefollowing patents and published patent applications: U.S. Pat. Nos.5,498,392; 5,486,335; and 5,304,487; and WO 96/04547. An analyticalsystem having an analytical module which connects to an expansionreceptacle of a general purpose computer is described in WO 95/02189. Asample typically present on an analytical rotor or other sample holder,may be placed in the receptacle and the computer used to controlanalysis of the sample in the module. Chemical analysis systems aredescribed in U.S. Pat. Nos. 5,510,082; 5,501,838; 5,489,414; 5,443,790;5,344,326; 5,344,349; 5,270,006; 5,219,526; 5,049,359; 5,030,418; and4,919,887; European published applications EP 299 521 and EP 6 031; andJapanese published applications JP 3-101752; JP 3-094158; and JP49-77693.

The disclosure of the present application is related to the followingco-pending applications, the full disclosures of which are incorporatedherein by reference, application Ser. Nos. 60/015498 (provisional),filed on Apr. 16, 1996; 08/671,987, filed on Jun. 28, 1996; 08/671,986,filed on Jun. 28, 1996; 08/678,436, filed on Jul. 3, 1996; and08/683,080, filed Jul. 16, 1996.

SUMMARY OF THE INVENTION

The present invention overcomes at least some of the deficienciesdescribed above by providing analytical and preparatory systems andmethods which employ an adapter to interface between a sample substrateand an analytical base unit. The sample substrate is usually amicrofluidic substrate but could be any other sample substrate capableof receiving test specimen(s) or starting material(s) for processing orproviding a detectable signal, where the base unit manages sample flow,reagent flow, and other aspects of the analytical and/or preparatorytechnique(s) performed on the substrate. The adapter allows a singletype of base unit, i.e. a base unit having a particular configuration,to interface with a large number of test and other substrates havingquite different configurations and to manage numerous specificanalytical and preparatory techniques on the substrates with little orno reconfiguration of the base unit itself.

The methods and apparatus will find use with both analytical andpreparatory techniques. By "analytical," it is meant that the assay orprocess is intended primarily to detect and/or quantitate an analyte oranalytes in a test specimen. By "preparatory," it is meant that theprocess is intended primarily to produce one or more products from oneor more starting materials or reagents. The remaining descriptionrelates mainly to the analytical methods and devices, but for the mostpart, all technology described will be equally useful for preparingmaterials for other subsequent uses.

In a first aspect, the present invention provides an analytical systemcomprising a base unit having an attachment region with a base interfacearray including at least one interface component therein. An adapterthat is configured to be removably attached to the attachment region ofthe base unit and has an adapter-base interface array which alsoincludes an interface component. The adapter-base interface array mateswith the base interface array when the adapter is attached to the baseunit, and at least some of the interface components in each of thearrays will couple or mate with each other. The adapter further includesa sample substrate attachment region having an adapter-sample substrateinterface array therein. The adapter-sample substrate interface arraywill usually also include at least one interface component (but in somecases could act primarily to position interface component(s) on the baseunits relative to interface component(s) on the sample substrate). Asample substrate is configured to be removably attached to the samplesubstrate attachment region of the adapter and itself includes a samplesubstrate interface array which usually includes at least one interfacecomponent. The interface component(s) in the sample substrate interfacearray will mate with corresponding interface component(s) in theadapter-sample substrate interface array and/or in the base interfacearray when the sample substrate is attached to the sample substrateattachment region.

By providing suitable interface components in each of the interfacearrays, power and/or signal connections may be made between the baseunit and the sample substrate in a virtually infinite number ofpatterns. In some cases, the base unit will provide only power andsignal connections to the adapter, while the adapter will provide arelatively complex adapter-sample substrate interface array for managingflow, other operational parameters, and detection on the samplesubstrate. In other cases, however, the base interface array on the baseunit may be more complex, including for example light sources,detectors, and/or high voltage power, and the adapter will be lesssophisticated, often acting primarily to position the sample substraterelative to interface components on the base unit, channeling voltages,and allowing direct communication between the base unit and the samplesubstrate.

Exemplary interface components include electrical power sources, analogsignal connectors, digital signal connectors, energy transmissionsources, energy emission detectors, other detectors and sensors, and thelike. Energy transmission sources may be light sources, acoustic energysources, heat sources, cooling sources, pressure sources, and the like.Energy emission detectors include light detectors, fluorometers, UVdetectors, radioactivity detectors, heat detectors (thermometers), flowdetectors, and the like. Other detectors and sensors may be provided formeasuring pH, electrical potential, current, and the like. It will beappreciated that the interface components will often be provided inpairs where a component in one array is coupled or linked to acorresponding component in the mating array in order to provide for thetransfer of power, signal, or other information. The interfacecomponents, however, need not have such paired components, and oftenenergy transmission sources or emission detectors will be providedwithout a corresponding interface component in the mating interfacearray.

The base unit, adapter and sample substrate will be configured so thatthey may be physically joined to each other to form the analyticalsystem. For example, the attachment region in the base unit may be acavity, well, slot, or other receptacle which receives the adapter,where the dimensions of the receptacle are selected to mate with theadapter. Similarly, the attachment region on the adapter may comprise areceptacle, well, slot, or other space intended to receive the samplesubstrate and position the substrate properly relative to the adapterand or base unit. The sample substrate will preferably employ mesoscalefluid channels and reservoirs, i.e. where the channels have at least onedimension in the range from 0.1 μm to 500 μm, usually from 1 μm to 100μm. The present invention, however, is not limited to the particularmanner in which the base unit, adapter, and substrate are attachedand/or to the particular dimensions of the flow channels on one samplesubstrate.

Although described thus far as a three-tiered system, it should beunderstood that the additional components or "tiers" could be utilized.For example, additional carriers or adapters could be utilized forproviding additional interface(s), such as a carrier for the samplesubstrate, where the carrier would be mounted within or attached to theadapter which is received on the base unit. Similarly, the attachmentregion in the base unit which receives the adapter may comprise adiscrete component which is itself removably or permanently affixed tothe base unit. Formation of the attachment region using a discretecomponent is advantageous since it facilitates standardization of thesystem. For example, the adapter-attachment region component could bemanufactured separately, optionally at a single location, and/orotherwise prepared to strict specifications, both of which would helpassure that the base units which incorporate such standardizedattachment regions will be compatible with all corresponding adapters.The standardized adapter-attachment region could also be adapted tointerconnect with other components of the base unit, such as heaters,cooling blocks, pin connections, and the like, thus facilitatinginterface with these elements. Thus, systems having four or more tiersfall within the scope of the present invention.

In a second aspect of the present invention, the analytical systemcomprises a base unit and a sample substrate, generally as describedabove. An adapter is configured to be removably attached to theattachment region of the base unit and includes an attachment region toremovably receive the sample substrate. The adapter holds the samplesubstrate in a fixed position relative to the base unit and provideseither (i) a connection path from an interface component in the baseinterface array to the substrate or (ii) a connection path from aninterface component in the sample substrate array to the base unit. Inthis aspect of the present invention, the adapter can act primarily toposition a sample substrate relative to the interface array in the baseunit. For example, if the base unit interface array includes a lightsource and/or light detector, the adapter can properly position thesample substrate relative to the light source/detector in order toperform a desired measurement. The adapter could optionally but notnecessarily provide further interface capabilities between the samplesubstrate and the base unit.

In yet another aspect of the present invention, adapters are providedfor use in combination with base units and sample substrates, asdescribed above. The adapter comprises an adapter body having anadapter-base interface array including at least one of power and signalconnector(s) disposed to mate with corresponding connector(s) in thebase interface array when the adapter is attached to the attachmentregion on the base unit. The adapter further includes a sample substrateattachment region having an adapter-sample substrate interface arrayincluding at least flow biasing connectors disposed to mate withcorresponding regions in the sample substrate interface array when thesample substrate is attached to the attachment region of the adapter.The flow biasing connectors will commonly be electrodes forelectrokinetic flow control in mesoscale and other microfluidic samplesubstrates, but could also be acoustic, pressure, or mechanicalflow-producing components. The adapter-sample substrate interface arraywill frequently include interface components in addition to the flowbiasing connectors, such as radiation emission and detection componentspositioned to interface with particular regions of the samplesubstrates.

The base unit may be self-contained, i.e. it may include all digitaland/or analog circuitry as well as user input/output interfaces whichare necessary for controlling an assay and producing assay results fromthe system. Often, however, it will be preferable to interface the baseunit with a general purpose or conventional computer, where the computercan provide some or all of the control analysis, and/or reportingfunction(s) as well as some or all of the user interface. Usually, thecomputer will be a standard personal computer or workstation whichoperates on a standard operating system, such as DOS, Windows® 95,Windows® NT, UNIX, Macintosh, and the like. The computer will be able toprovide a number of standard user input devices, such as a keyboard,hard disk, floppy disk, CD reader, as well as user outputs, such asscreens, printers, floppy disks, writable CD output, and the like. Useof the computer is particularly advantageous since it can significantlyreduce the cost of the base unit and allow significant upgrading of thecomputer component of the system while using the same base unit. Despitethese advantages, in some instances it may be desirable to incorporatethe interface and digital circuitry of a computer into the base unit ofthe present invention, allowing all of the capabilities of aconventional digital computer, but with perhaps less flexibility.

When the system of the present invention is controlled via digitalcircuitry, i.e. using a separate conventional computer interfaced withthe base unit or using digital control circuitry incorporated within thebase unit, it will usually be desirable to provide at least a portion ofthe operating instructions associated with any particular adapter and/orany particular sample substrate and assay format in a computer-readableform, i.e. on a conventional computer storage medium, such as a floppydisk, a compact disk (CD ROM), tape, flash memory, or the like. Themedium will store computer readable code setting forth the desiredinstructions, where the instructions will enable the computer (which maybe a separate or integral computer) to interface with the base unit andto control an assay performed by the base unit upon the sample presenton a sample substrate held by an adapter received on the base unit. Thepresent invention thus comprises the computer program itself in the formof a tangible medium, e.g. disk, CD, tape, memory, etc., which may beused in combination with the system of the present invention. Thepresent invention further comprises systems which include an adapter asset forth above in combination with the tangible medium storing thecomputer instructions described above. The present invention stillfurther comprises systems which are combinations of one or more samplesubstrates as generally set forth above, together with a tangible mediumsetting forth computer readable code comprising instructions as setforth above.

The computer program may be provided to the user pre-loaded onto thedesired medium, usually a floppy disk or a CD ROM, or may alternativelybe downloaded onto the medium by the user from a central location via anetwork, over phone lines, or via other available communication andtransmission means. The program will then be incorporated onto themedium and be available for use in the systems and methods of thepresent invention.

In a still further aspect in the present invention, a method forconfiguring an analytical system comprises providing a base unit havingan attachment region including at least one interface component therein.An adapter is removably attached to the attachment region of the baseunit so that an interface component on the adapter mates with acorresponding interface component on the base unit. The adapter includesa sample substrate attachment region having at least one interfacecomponent therein, and a sample substrate is removably attached to thesample substrate attachment region on the adapter so that an interfacecomponent on the sample substrate mates with a corresponding interfacecomponent on the adapter. Usually, but not necessarily, the adapter isremovably attached to the base unit by placing the adapter within areceptacle on the base unit, and the sample substrate is removablyattached to the adapter by placing the sample substrate within areceptacle on the adapter. The sample substrate will preferably be amicrofluidic device having a plurality of channels connecting aplurality of reservoirs and including flow biasing regions positioned atone of the reservoirs and/or channels. The base unit may then direct ormanage flow in the substrate by providing flow control signals to theadapter. The flow control signals energize flow biasing regions on theadapter whereby corresponding flow biasing regions on the substrate areenergized to control flow through the channels and among the reservoirs.For example, the flow control may be effected by electrically biasingelectrodes on the sample substrate to cause electrokinetic flow control.Alternatively, the energizing step may comprise acoustically driving theflow biasing regions on the sample substrate. Usually, the adapter willinclude electromagnetic radiation sources and detectors for signalgeneration and detection in a variety of analytical techniques. Any ofthe above control steps may be implemented by providing computerreadable code to an integral or separate computer which controls theanalytical system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a first embodiment of an analytical systemincorporating the features of the present invention.

FIG. 2 illustrates a second embodiment of an analytical systemincorporating the features of the present invention.

FIG. 3 is a block diagram illustrating the information flow betweenvarious components of the system of the present invention.

FIG. 4 illustrates an exemplary analytical system incorporating thecomponents of the system of the present invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Analytical systems according to the present invention comprise a baseunit, an adapter, and a sample substrate. Each of these parts of thesystem will be described in detail below. In general, the analyticalsystems will be configured to receive and analyze a wide variety ofsamples and specimens. For example, samples may be biological specimensfrom a patient, but they may also be a wide variety of other biological,chemical, environmental, and other specimens having a component to becharacterized or analyte to be detected. The analytical systems may beused to implement numerous specific analytical and/or preparativetechniques, such as chromatography, PCR, LCR, enzymatic reactions,immunologic reactions, and the like. Samples will usually be liquid orbe liquified prior to testing, and will frequently undergo a chemical orbiochemical reaction prior to analysis. The analytical systems mayprovide for a variety of manipulations of the sample in addition tochemical and biological reactions, such as mixing, dispensing, valving,separation, heating, cooling, detection, and the like. The analyticalsystems may rely on numerous known detection techniques such asspectrophotometry, fluorometry, radiometry, magnatometry, galvanometry,reflectrometry, ultrasonic detection, mephlometry, electrophoreticmeasurement, temperature measurement, pressure measurement,potentiometric measurement, amperometric measurement, and the like. Inthe exemplary and preferred embodiments below, sample manipulation anddetection are performed in microfluidic substrates where the sample ismanipulated between and among very small volume reservoirs and flowchannels formed in the substrate. Usually, all flow and test conditionson the substrate will be controlled through the base unit and theadapter, as described in more detail below.

The base unit of the present invention will typically comprise anenclosure or frame which may be intended for mounting, e.g. on thefloor, on a counter, in a rack, or in any other conventional manner, orwhich may be portable or hand-held. The base unit will usually includeat least power and/or signal transmission circuits, and will usuallyinclude signal processing capability for helping to analyze and/or storedata received from the adapter as described in more detail below. Thebase unit will usually further include a microprocessor for helpingmanage both its substrate management and data collection duties.Optionally, information displays in the form of video monitors,alphanumeric displays, printers, LED displays, and the like, may beprovided on or in the frame, often together with data entry devices,such as keyboards, touch screens, and the like. In the exemplaryembodiments, however, the base unit includes only a plug connector forinterfacing with an external computer, where the computer provides thenecessary input and output devices. In such cases, the base unit willoften, but not necessarily, include an internal microprocessor forcontrolling or helping to control the internal operations of the baseunit and adapter. Alternatively, a microprocessor could be provided inthe adapter, with the base unit providing only interface functionsbetween the adapter and the computer. In other cases, all controlfunctions will be managed through the separate computer with the baseunit and adapter providing only distribution and interface functions.Again, it should be appreciated that availability of both the base unitand the adapter provides for a very wide range of specific designs withdifferent functions being selectively distributed between the adapterand the base unit for particular assays and sample substrate designs.

The base unit will include an attachment region for removably securingthe adapter. The attachment region on the base unit has a base interfacearray including at least one, and usually multiple, interfacecomponent(s) intended to provide power and/or information communicationwith the adapter. The interface component(s) comprise a wide variety ofdevices as described in more detail below. The attachment region may beany feature or structure on the enclosure or frame of the base unitwhich can removably attach the adapter. The attachment region willusually be constructed so that the adapter can be connected in a uniqueconfiguration only so that the base interface array will be uniquelyconfigured relative to the adapter. The attachment region may have awide variety of forms, such as receptacles, wells, slots, trays (similarto a CD tray), or the like. Often, the attachment region will define areceptacle having dimensions which correspond to the outer peripheraldimensions of the adapter so that the adapter may be held in a desiredorientation relative to the base unit. Alternatively, or in addition,pegs, pins, latches, or other attachment elements may be provided tohold the adapter on the base unit in a desired orientation.

The adapter will also comprise an enclosure or frame, although theenclosure or frame will usually be significantly smaller than that ofthe base unit. The enclosure or frame will be adapted to be received onor in the attachment region of the base unit, as generally discussedabove, and will itself include an attachment region for removablysecuring the sample substrate. The attachment region on the adapter maytake any of the forms discussed above for the attachment region on thebase unit, and it will usually be necessary for the attachment region toimmobilize the sample substrate in a particular orientation relative tothe adapter.

The adapter will include an adapter-base interface array which meetswith or couples to the base interface array when the adapter is mountedin the attachment region on the base unit. The adapter-base interfacearray will include at least one interface component which mates with acorresponding interface component within the base interface array,usually to provide for power and/or signal connection between the baseunit and the adapter. The interface component(s) may provide for a widevariety of additional interconnections, and will be described in greaterdetail below.

The sample substrate attachment region will include an adapter-samplesubstrate interface array intended to mate with or couple to a samplesubstrate interface array on the sample substrate when the samplesubstrate is attached to the attachment region. The adapter-samplesubstrate interface array will itself include at least one interfacecomponent which may be any of the components described in more detailbelow. Usually, the adapter-sample substrate interface array willinclude multiple interface components which are disposed or distributedin a pattern selected to mate with at least some corresponding interfacecomponent in the sample substrate array on the sample substrate.

The sample substrate may comprise any one of a variety of knownanalytical devices or articles intended for receiving a sample andprocessing the sample in some manner to provide a detectable outputwhich can be related to a sample characteristic, e.g. the presence of ananalyte, the composition or nature of a molecule present in the sample(e.g. protein or nucleic acid sequence), or the like. The presentinvention is particularly intended for use with microfluidic samplesubstrate of the type described in U.S. Pat. Nos. 5,498,392; 5,486,355;5,304,487; and published PCT application WO 96/04547, the fulldisclosures of which are incorporated herein by reference. Suitablemicrofluidic substrates are also described in commonly assignedco-pending pending application Ser. Nos. 08/761,987, filed Jun. 28,1996, and 08/845,759, filed Apr. 25, 1997, the full disclosures of whichare incorporated herein by reference.

A particular advantage of the present invention is that the adapter canbe configured to receive any one of a variety of specific samplesubstrate configurations. In that way, the designer of the samplesubstrate is free to optimize the size, design, flow paths, and otherfeatures of the sample substrate without undue regard to the nature ofthe base unit. Within a wide latitude, most specific design features ofa sample substrate may be accommodated by appropriately designing anadapter. While this advantage is available, it is also possible that thedesign of the sample substrate take into account specificcharacteristics and design features of either or both of the base unitand adapter. It will be appreciated that the system architectureemploying the adapter as an interface between the sample substrate andthe base unit provides for significant design flexibility.

The sample substrate will have dimensions and other characteristicsselected to permit removable attachment to the attachment region, asgenerally discussed above. Sample substrate will further include thesubstrate interface array which includes at least one interfacecomponent disposed to mate with a corresponding interface component onthe adapter-sample substrate interface array on the adapter. Again, theinterface components may comprise any of a wide variety of particulardevices and elements, as discussed in more detail. The interfacecomponents on the adapter and sample substrate will generally be able toprovide for both flow control management of the sample and other liquidreagents present in and applied to the sample substrate and will furtherprovide for interconnection of power and signals between the adapter andsample substrate.

As used herein and in the claims, the phrase "interface component"refers to any one of a wide variety of discrete components or regionspresent in the interface arrays on the base unit, adapter, or samplesubstrate. Interface components will generally provide for electrical orother energy transfer, analog or digital signal transfer, energytransmission, energy emission detection, and the like.

Electrical connections, both for power and signal transfer, willgenerally comprise conventional connectors in the form of electrodes,pins, plugs, zero insertion force (ZIF) connectors, and the like. Suchelectrical connections will usually require mating connectors in two ofthe interface arrays which are brought together when the system is puttogether. The electrical connectors will often be present on a surfaceor edge of the interface array so that corresponding components will beengaged against each other when the adapter is mounted in the base unitor the substrate is mounted on the adapter. Similarly, surface or edgeelectrodes in the adapter-sample substrate interface array may beprovided to mate with corresponding surface or edge electrodes on thesample substrate. The electrodes on the sample substrate may then beconnected internally in the substrate to the desired reservoirs or fluidflow channels in order to effect electrokinetic flow control, asdescribed in the previously incorporated patents and patentapplications. In other cases, however, it will be desirable to provideinterface components in the adapter-sample substrate interface arraywhich directly contact the fluid to be electrokinetically controlled.For example, probes or pins may be provided on the adapter which willpenetrate into open wells or through septums on the sample substrate inorder to permit direct contact and application of electrical potential.A specific example of such connectors are shown in FIG. 2 below.

The energy transmission sources will generally be intended to eitherenergetically excite a region on the test substrate or provide energy toinitiate fluid flow on the sample substrate. The energy may take a widevariety of forms, including light, such as visible light and UV light,acoustic energy, heat, cooling, pressure, mechanical energy, electricalenergy, and the like. In the case of sample detection, the energytransmission source may be light or other radiation intended to excite aspecies or label to be detected. Heating/cooling may be provided to helpeffect or condition a particular chemical reaction. Acoustic, pressure,and mechanical energy may be provided to directly effect fluid flow inchannels of microfluidic sample substrates. It will be appreciated thatsuch energy transmission sources do not necessarily have correspondinginterface components in an adjacent interface array. Instead, energytransmission will often be directed generally at regions on the samplesubstrate where energy is to be received.

Energy emission detectors may be provided, usually on the adapter and/orthe base unit, to detect energy emitted from the sample substrate. Forexample, detection reactions may result in the emission of light viafluorescence, luminescence, radiation, or other energy emissions whichneed to be detected and/or quantified in order to perform particularanalysis. The appropriate detection components may be provided in theadapter and/or base unit, and the adapter relied on to appropriatelyalign the substrate the detectors.

A particular class of interface components employed by the analyticalsystem of the present invention are referred to as "flow biasingconnectors." Flow biasing connectors are intended to identify thoseinterface components which can effect fluid flow on sample substrates,particularly on microfluidic substrates having a network of flowchannels and reservoirs. For microfluidic substrates employingelectrokinetic flow management, the flow biasing connectors on theadapter will usually be electrodes, probes, pins, or the likedistributed within or on the adapter sample substrate interface array tomate with the network of flow channels and reservoirs in the samplesubstrate as generally described above and in the previouslyincorporated references. The electrodes will usually have correspondingelectrode terminals present within the interface array on the samplesubstrate so that the electrode terminals may be interconnected tocorresponding electrical connectors on the adapter-sample substrateinterface array on the adapter (or in rare cases on the base interfacearray on the base unit). In other cases, as described above, the flowbiasing connectors may be probes or pins on the adapter which arepositioned to directly engage fluids present on or in the samplesubstrate. For example, an array of pins may be provided on a hinged lidor cover on the adapter plate so that the sample substrate may bepositioned on the adapter and the lid cover thereafter closed in orderto penetrate the pins into open sample wells on the substrate. Thesample wells, of course, need not be open and could be covered with anypenetratable membrane or septum which is pierced by the pins when thecover is closed. Other flow biasing connectors include acoustic energysources (piezoelectric transducers) positioned within the adapter-samplesubstrate interface array so that they engage the sample substrate atpositions intended to induce fluid flow through the flow channels. Otherflow biasing connectors include pressure sources which can initiate flowby pressurization, mechanical energy sources, which can effectmechanical pumping of liquids through the flow channels, and the like.

Referring now to FIG. 1, a first exemplary analytical system 10constructed in accordance with the principles of the present inventioncomprises a base unit 12, an adapter 14, and a sample substrate 16. Thebase unit 12 includes a pin socket 20 for mating with a plug 22 on abottom surface of the adapter 14. A computer port 24 is provided formating with conventional serial or parallel inputs on general purposecomputers, such as personal computers, work stations, and the like.Usually, the base 12 will include at least signal processing andconditioning components, such as analog-to-digital converters forreceiving analog data from the adapter 14 and converting that data todigital form for transmission to the computer. In other cases, however,the computer may be adapted to directly convert analog signals todigital data. The base unit 12 and/or adapter 14 could also be providedwith digital-to-analog converters for controlling power, flow, or anyother parameter directly from digital signals from the computer. Theadapter 14 may also include internal microprocessor(s) for further datamanipulation. The adapter 14 may also include a power input, for eitherline AC current and/or low voltage DC current (which may be provided bya power supply in the base unit 12). The pin socket 20 will usuallyprovide for interface for both power and signal exchange between thebase unit 12 and the adapter 14. Locating pins 28 are provided on anupper surface of the base 12 to engage locating holes 30 on the adapter14. Thus, the entire upper surface of the base unit 12 will provide theattachment region for the adapter 14 while the pin socket 20 willgenerally provide the adapter-base interface array with the individualpins providing the interface components.

A plug 22 comprises the adapter-base interface array on the adapter 14.The plug 22 provides for both power and signal connections to the baseunit 12 and the adapter further provides an optical source and detector34 and a heating/cooling element 36, both of which mate to particularregions on the sample substrate 16, as described further below. Theadapter 14 further includes an edge connector 40 which includes a numberof electrodes 42 which mate with corresponding electrodes 44 on an edgeof the sample substrate 16. The sample substrate 16 is removablyattached to the adapter 14 by sliding the substrate between a pair ofguides 46 which are formed by parallel L-shaped channels on the uppersurface of the adapter 14. When the sample substrate 16 is fullyinserted between the guides 46 with the electrodes 44 received in theedge connector 40, a reaction site 50 on the sample substrate 16 isaligned with the optical source of detector 34 on the adapter 14 and athermal treatment region 52 is aligned with the heater/cooler 36 on theadapter. Thus, the optical source detector 34, heater/cooler 36, andedge connector 40 comprise interface components in the attachment regionof the adapter 14.

The sample substrate 16 comprises a plurality of sample and reagentwells 60, each of which is coupled to an electrode 44 in the interfacearray. In this way, sample flow on the sample substrate can becontrolled through the base unit 12 and the adapter 14 to control powerthrough the electrodes 42. It will be appreciated that the power may beprovided directly by the base unit 12, in which case the adapter 14 actsmerely to distribute the power. Alternatively, the base unit 12 mayprovide information to the adapter, and the adapter 14 generate thepower internally which is distributed through the electrodes 42. Ineither case, sample flow among the reservoirs and a flow channel network66 is controlled in a desired manner. A portion of the sample and mixedreagents will flow through the heating/cooling region 52, where it willbe appropriately treated. Again, the amount of heat or cooling suppliedby region 36 is provided and controlled by a combination of the baseunit 12 and adapter 14, where specific functions may be provided byeither of those two components. An output signal resulting from one ormore reactions is eventually read at the reaction region 50 by theoptical source/detector 34. Output of the optical detector 34 will bepassed back to the base unit 12 through the pin socket 20 and male plug22. The optical detector will usually produce an analog signal, and suchanalog signal may be converted to digital in any of the adapter 14, baseunit 12, or external computer (not shown).

A second exemplary embodiment 100 of the analytical system of thepresent invention is illustrated in FIG. 2. The analytical system 100includes a base unit 112, an adapter 114, and a sample substrate 116.The base unit 112, is similar in many respects to base unit 12 in FIG.1, and includes locating pins 128, a pin socket 120, and a computer port124. Base unit 112, however, further comprises an opticalsource/detector 134. This is different than the analytical system 10,where the optical source/detector 34 was provided as part of the adapter14.

The adapter 114 comprises a plate 115 having an aperture 117 in itscenter. When the adapter 114 is mounted on the base unit 112, theaperture 117 will lie generally over the optical source/detector 134.Adapter 114 further includes a hinged cover 119 which is used to coverand position the sample substrate 116 on top of the plate 115. When thesample substrate 116 is positioned, and the hinge cover 119 closed, aplurality of probes 121 on a lower surface of the cover will penetrateinto sample and reagent wells 160 on the sample substrate 116. The wells160 may be completely open or may be covered by a penetratable membraneor septum. The probes 121 will thus be immersed and in direct contactwith the liquids present in the wells 160. In that way, electricalbiasing can be provided in order to effect electrokinetic flowmanagement through the channel network 166 on the sample substrate 116.

The sample substrate 116 includes a reaction zone 150 which will usuallybe at least partly transparent or translucent to permit light from theoptical source detector 134 to reach the fluid in the region and topermit emitted or detected light to leave the region. Such incident andemitted light from region 150 will pass through the aperture 117 in theadapter 114 so that it may be directly coupled to the opticalsource/detector 134. Again, this is a difference with the analyticalsystem 10 of FIG. 1 where detection was performed directly between theadapter 14 and the sample substrate 16.

It should be appreciated that the exemplary analytical systems 10 and100 are intended to be representative of a virtually infinite number ofpossible system configurations. Use of an adapter 14 or 114 permits thevarious power, signal, and other functions of the analytical system tobe included in any one of the adapter, base unit, substrate, or externalcomputer in virtually any manner so that any particular analyticaltechnique can be optimally supported by the system.

Referring now to FIG. 3, a system 200 according to the present inventioncan be configured in a wide variety of ways. For example, a base unit212 may comprise a single monolithic instrument containing all controland analysis components necessary for performing an assay (incombination with adapter 214 and sample substrate 216), needing only tobe connected to line current or other power source. The base unit 212,however, will be connected to a general purpose computer 220, e.g. apersonal computer or work station, which provides at least a portion ofthe input/output, control, and computational functions of the system200. The computer 220 may be connected by any conventional connectors,typically using serial or parallel input ports. The computer will beprogrammed using software 222, which may be in the form of anyconventional computer medium. The software will comprise instructionsfor all or a portion of the computer functions. For example, thesoftware may comprise the operating system utilized in performing allassays using the system of the present invention. Alternatively, thecomputer may utilized a conventional operating system capable ofcontrolling real time functions, as set forth above. The system testsoftware 222 will usually include system instructions which are generaland apply to many assays as well as system instructions which arespecific for any particular assay. The instructions may be included in asingle disk or other medium, or may be included in multiple disks whichmay then be combined in a desired manner for performing a particularassay. Alternatively, the test software may be downloaded into the baseunit and/or onto a storage medium via a network, the internet, orotherwise as set forth above. The system software will include functionssuch as system initialization, assay format, computational instructions,user/patient input instructions, and the like.

Thus, it can be seen, that the base unit 212 and computer 220 willgenerally be useful for performing many different types of assays, whilethe adapter 214 and sample substrate 216 will be more specificallydirected at particular assay(s). One type of adapter 214 may becompatible with multiple sample substrates 216 intended for performingtwo or more different assays, where the system test software 222 canenable the adapter 214 and base unit 212 to properly interface with thesample substrate 216. Systems according to the present invention willthus further comprise the combination of test hardware 222 with eitheran adapter 214, sample substrate(s) 216, or both. That is, a useralready possessing a monolithic base unit 212 or combination base unit212 and computer 220, may later acquire the combination of system testsoftware 222 and adapter 214 intended to perform a particular assay orassays. By then mounting the adapter 214 on the base unit and loadingthe software 222 onto the computer 220/base unit 212, the system will beconfigured to receive sample substrates to analyze particular testspecimens for the desired analyte. Alternatively, when an adapter 214 issuitable for two or more assays, the user may later acquire thecombination of test software 222 and sample substrate(s) 216 whichenable the preexisting combination of computer 220, base unit 212, andadapter 214 to perform a new assay. In some cases, the combination ofadapter 214, sample substrate(s) 216, and system test software 222 willalso be provided to the user.

Referring now to FIG. 4, an exemplary system 300 configuration isillustrated. The system 300 comprises a base unit 312, an adapter 314,and a sample substrate 316. Additionally, a universal adapter 320 isprovided as a discrete component for removable or permanent mountingonto the base unit 312. The universal adapter 320 defines the attachmentregion on the base unit 312 for receiving the adapter 314. Base unit 312provides system functions, such as an optical source/detector 322 and aheater plate 324. The universal adapter 320 is mounted over the heaterplate 324 onto a support surface 326 of the base unit 312. The base unit312 is then ready to removably receive adapter plate(s) 314 which inturn is ready to receive sample substrates 316. The various interfacesamong the system components may follow any of the patterns describedabove in connection with the systems of FIGS. 1 and 2. Use of theuniversal adapter 320 is advantageous since it facilitatesstandardization of the interface between the base unit 312 and theadapter 314. Also, a single base unit 312 (or base unit design) can beinterfaced with an even wider range of adapters 314 by employingdifferent classes or types of universal adapters, each of which candisplay alternative functionalities and interconnection patterns.

Although the foregoing invention has been described in some detail byway of illustration and example, for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

What is claimed is:
 1. An analytical system comprising:a samplesubstrate having a plurality of mesoscale channels disposed therein, theplurality of channels connecting a plurality of reservoirs, each of theplurality of channels having at least one cross-sectional dimensionbetween about 0.1 and 500 μm; a base unit comprising an electrical powersupply; a sample substrate interface array attached to the base unit andcomprising:a sample substrate attachment region including a plurality ofelectrical connectors disposed thereon, the electrical connectors beingelectrically coupled to the electrical power supply and being positionedwithin the substrate attachment region to provide electrical connectionbetween the plurality of reservoirs and the electrical power supply whenthe substrate is placed, in the substrate attachment region wherein theelectrical connectors comprise pin electrodes disposed on the interfacearray, the pin electrodes being positioned to directly engage fluidspresent in the reservoirs; and an energy emission detector disposed inthe base unit and positioned to detect energy emitted from at least oneof the channels disposed in the sample substrate, when the samplesubstrate is placed in the sample substrate attachment region.
 2. Theanalytical system of claim 1, wherein the substrate attachment regioncomprises a hinged cover, the pin electrodes being positioned on thehinged cover to directly engage fluids present in the reservoirs whenthe cover is closed over the sample substrate.
 3. The analytical systemof claim 1, wherein the energy emission detector comprises an opticaldetector.
 4. The analytical system of claim 3, wherein the opticaldetector comprises an optical source/detector.
 5. The analytical systemof claim 4, wherein the optical source/detector comprises a fluorescencedetector.
 6. The system of claim 1, further comprising a computeroperably coupled to the base unit, the computer comprising appropriatesoftware for instructing interfacing between the base unit and thesample substrate.
 7. The analytical system of claim 1, wherein thesample substrate interface array is disposed on an adapter, the adapterbeing removably attached to the base unit, the adapter providingelectrical connection between the plurality of electrical connectors onthe sample substrate interface array and the electrical power supply inthe base unit.
 8. An analytical system comprising:a sample substratehaving a plurality of mesoscale channels disposed therein, the pluralityof channels connecting a plurality of reservoirs, each of the pluralityof channels having at least one cross-sectional dimension between about0.1 and 500 μm; a base unit comprising an electrical power supply; asample substrate interface array attached to the base unit andcomprising:a sample substrate attachment region including a plurality ofelectrical connectors disposed thereon, the electrical connectors beingelectrically coupled to the electrical power supply and being positionedwithin the substrate attachment region to provide electrical connectionbetween the plurality of reservoirs and the electrical power supply whenthe substrate is placed in the substrate attachment region, wherein theelectrical connectors on the sample attachment region compriseelectrical contacts that are positioned to establish electrical contactwith a plurality of corresponding electrical contacts on themicrofluidic device when the microfluidic device is placed in thesubstrate attachment region, the electrical contacts on the microfluidicdevice providing an electrical connection to the plurality ofreservoirs; and an energy emission detector disposed in the base unitand positioned to detect energy emitted from at least one of thechannels disposed in the sample substrate, when the sample substrate isplaced in the sample substrate attachment region.
 9. The analyticalsystem of claim 8, wherein the substrate attachment region comprises ahinged cover, the electrical contacts on the substrate attachment regionbeing positioned on the hinged cover to contact the plurality ofcorresponding electrical contacts on the sample substrate when thehinged cover is closed.
 10. The analytical system of claim 8, whereinthe electrical connectors on the sample attachment region are selectedfrom pins, plugs, zero insertion force (ZIF) connectors and edgeconnectors.
 11. The analytical system of claim 8, wherein the energyemission detector comprises an optical detector.
 12. The analyticalsystem of claim 11, wherein the optical detector comprises an opticalsource/detector.
 13. The analytical system of claim 12, wherein theoptical source/detector comprises a fluorescence detector.
 14. Thesystem of claim 8, further comprising a computer operably coupled to thebase unit, the computer comprising appropriate software for instructinginterfacing between the base unit and the sample substrate.
 15. Theanalytical system of claim 8, wherein the sample substrate interfacearray is disposed on an adapter, the adapter being removably attached tothe base unit, the adapter providing electrical connection between theplurality of electrical connectors on the sample substrate interfacearray and the electrical power supply in the base unit.